Cancer is a disease for which many potentially effective treatments are available. However, due to the prevalence of cancers of various types and the serious effects it can have, more effective treatments, especially those with fewer adverse side effects than currently available forms of treatment, are needed.
This invention relates to pharmaceutical compositions useful in treating cancer in a mammal. The pharmaceutical compositions of the present invention comprise two compounds: a first compound which is paclitaxel, taxotere or a modified taxane or taxoid analog and a second compound, which is a compound of Formula I:
R1R2Nxe2x80x94CHXxe2x80x94COxe2x80x94Axe2x80x94Bxe2x80x94Dxe2x80x94(E)sxe2x80x94(F)txe2x80x94(G)uxe2x80x94Kxe2x80x83xe2x80x83(I)
Formula I is discussed in detail below. Some examples of compounds of Formula I are specifically presented herein. For example, compounds of Formula I can be those in which R1 and R2 are each methyl or ethyl; X is isopropyl, sec-butyl or tert-butyl; s is 1; t and u are each 0; A is valyl, isoleucyl or 2-tert-butylglycyl; B is N-methylvalyl, 1-isoleucyl or 2-tert-butylglycyl; D is thiazolidinylcarbonyl, 3,4-dehydroprolyl or prolyl; E is prolyl, thiazolidinyl-4-carbonyl, homoprolyl, hydroxyprolyl or 3,4-dehydroprolyl; and K is a substituted amino moiety having the formula R5xe2x80x94Nxe2x80x94R6, wherein R5 is hydrogen or C1-C4-alkoxy and R6 is a monovalent radical such as (1)- or (2)-adamantyl; (CH2)v-phenyl with v=1; xcex1,xcex1-dimethylbenzyl; a C1-C12 linear or branched hydroxyalkyl group, such as xe2x80x94C(CH3)2xe2x80x94CH2xe2x80x94CH2xe2x80x94OH, also referred to as 3-hydroxy-1,1-dimethylpropyl; a C3-C10 cycloalkyl group, such as bicyclo[3.3.0]octa-1-yl, 1-methylcyclopentyl or 1-methylcyclohexyl; or a C1-C12 linear or branched alkyl group, such as
xe2x80x94C(CH3)3, also referred to as tert-butyl; 
xe2x80x83also referred to as 1,1-dimethylpropyl; 
xe2x80x83also referred to as 1-methyl-1-ethylpropyl; 
xe2x80x83also referred to as (S)- or (R)-1-methyl-2,2-dimethyl-propyl; 
xe2x80x83also referred to as (S)- or (R)-1-ethyl-2-methylpropyl; 
xe2x80x83also referred to as 1-isopropyl-2-methylpropyl; or
xe2x80x94C(CH3)2xe2x80x94CH(CH3)2, also referred to as 1,1-dimethyl-2-methylpropyl;
xe2x80x94CH(CH3)2, also referred to as isopropyl;
xe2x80x94CH(CH3)CH2CH3, sec-butyl [(S) or (R)]; or
xe2x80x94CH(CH3)CH(CH3)2, also referred to as 1,2-dimethylpropyl.
Each compound is present in the pharmaceutical composition in an effective amount. The pharmaceutical composition can include one or more of each type of compound (e.g., one or more of the first type of compound, such as paclitaxel or paclitaxel and taxotere and one or more compounds of Formula I).
This invention also relates to methods of treating cancer in a mammal in which the pharmaceutical compounds described herein are used. In the method of the present invention, the two compounds are administered in the pharmaceutical composition or as individual/separate compounds which are given sufficiently close in time to have the desired effect.
It has been discovered that, surprisingly the combination of paclitaxel, taxotere or a modified taxane or taxoid analog as described herein and a compound having Formula I as described herein provides enhanced or therapeutically synergistic anticancer effects in vivo. For purposes of this invention, two drugs are considered therapeutically synergistic if a combination regimen produces a significantly better tumor cell kill than the best constituent when it is administered alone at optimal or maximum tolerated doses. Differences in tumor cell kill less than half a decade are not considered signficant.